Abstract

Curcumin, a naturally occurring compound, is widely known for its anti-oxidant, anti-inflammatory, anti-proliferative and various other activities in cell culture studies. However, it has elicited only limited efficacy in animal and in clinical studies despite high doses, due to its poor oral bioavailability. Recently, we showed that continuous systemic delivery of curcumin by subcutaneous polymeric implants can circumvent issues associated with bioavailability. In this study we investigated potential of curcumin delivered via the implants and diet against 17β-estradiol (E2)-mediated mammary carcinogenesis. Implants were prepared using polycaprolactone and polyethylene glycol (65:35) alone or with curcumin (20%, w/w). The implants exhibited biphasic release kinetics in vitro with a burst release (7%) in the first week, followed by a more controlled release. In vivo drug release followed the same kinetics as the in vitro release, except that the total amount released was 1.8-fold higher presumably due to sink conditions. To determine the anticarcinogenicity potential, female ACI rats were either administered curcumin via the diet or were subcutaneously grafted with two 2-cm implants (20% drug load) 4 days prior to grafting a subcutaneous E2 silastic implant (1.2 cm, 9 mg E2). Implants were changed after nearly 4 ½ months to provide higher curcumin dose at the appearance of palpable tumors. The animals were euthanized after 3 weeks, 3 months and after the tumor incidence reached >80% (6 months) in control animals. Curcumin administered via implants resulted in significant reduction in both the tumor volume (184±198 mm3 vs 280±141 mm3; p=0.0283) and tumor multiplicity (5±3 versus 2±1; p=0.001); the dietary curcumin, however, was ineffective. Further, serum E2 concentration and E2-mediated increase in plasma prolactin were also found to be significantly reduced by curcumin implants but not with dietary curcumin. Analysis of plasma by HPLC showed higher curcumin levels (2.4 nM) via implant route as compared to diet at ∼10-20 fold lower doses both after 3 weeks and 3 months of treatment. Similarly, higher levels of curcumin were detected in liver tissue also by the implant route than dietary administration after both 3 weeks (60±28 versus 40±20 ng/g) and 6 months (32±15 versus 21±9 ng/g). Dietary curcumin increased hepatic CYP1A and CYP1B1 activity without any effect on CYP3A4 activity whereas curcumin implants increased both CYP1A and CYP3A4 activity but decreased CYP1B1 activity in presence of E2. Since, CYP1A and 3A4 metabolize most of the E2 to its non-carcinogenic 2-OH metabolite and CYP1B1 produces potentially carcinogenic 4-OH metabolite, it appears that favorable modulation of these CYPs via systemic curcumin delivery could be one of the mechanisms that resulted in the reduced E2 mediated mammary carcinogenesis (Supported from CA-118114 and Agnes Brown Duggan Endowment).